WO1995001791A2 - Utilisation de l'efaroxan et de ses derives pour la fabrication de medicaments destines au traitement des maladies neurodegeneratives - Google Patents

Utilisation de l'efaroxan et de ses derives pour la fabrication de medicaments destines au traitement des maladies neurodegeneratives Download PDF

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Publication number
WO1995001791A2
WO1995001791A2 PCT/FR1994/000841 FR9400841W WO9501791A2 WO 1995001791 A2 WO1995001791 A2 WO 1995001791A2 FR 9400841 W FR9400841 W FR 9400841W WO 9501791 A2 WO9501791 A2 WO 9501791A2
Authority
WO
WIPO (PCT)
Prior art keywords
hydrogen atom
propyl
chloro
alzheimer
neurodegenerative diseases
Prior art date
Application number
PCT/FR1994/000841
Other languages
English (en)
French (fr)
Other versions
WO1995001791A3 (fr
Inventor
Francis Colpaert
Michael Briley
Thierry Imbert
Original Assignee
Pierre Fabre Medicament
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pierre Fabre Medicament filed Critical Pierre Fabre Medicament
Priority to DE69421705T priority Critical patent/DE69421705T2/de
Priority to CA002166781A priority patent/CA2166781A1/fr
Priority to EP94921698A priority patent/EP0707477B1/de
Priority to JP50386595A priority patent/JP3494651B2/ja
Priority to NZ268914A priority patent/NZ268914A/xx
Priority to US08/581,516 priority patent/US5661172A/en
Priority to AU72308/94A priority patent/AU688346B2/en
Priority to DK94921698T priority patent/DK0707477T3/da
Publication of WO1995001791A2 publication Critical patent/WO1995001791A2/fr
Publication of WO1995001791A3 publication Critical patent/WO1995001791A3/fr
Priority to GR20000400227T priority patent/GR3032531T3/el

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present invention relates to the use of Efaroxan and its derivatives to obtain a neuroprotective medicament, intended for the treatment of senile dementia of the Alzheimer type, of pre-Alzheimer syndrome, of supra-nuclear progressive paralysis and others neurodegenerative diseases.
  • Alzheimer's disease is a progressive neurodegenerative disease affecting particularly but not exclusively the central cholinergic system (Nucleus basalis de Meynert) resulting in a loss of cognitive faculties, a loss of intellectual capacities, behavioral and personality disorders .
  • the central cholinergic system Nucleus basalis de Meynert
  • Alzheimer's disease There is currently no satisfactory treatment either for the treatment of symptoms or to slow its progression. Diagnosing the disease is difficult, and you can never be sure to diagnose Alzheimer's disease itself. It is in particular the anatomo-histological analysis carried out post-mortem by, among other things, the detection of senile extraneuronal plaques and intraneuronal neurofibrillary tangles, which can allow the disease to be diagnosed without ambiguity. Alzheimer's. It is also associated with loss of cell bodies and depletion of neurotransmitters, in particular acetylcholine. In the absence of this histological and biochemical evidence, the clinical characteristics lead to the diagnosis of a neurodegenerative disease, of the pre-Alzheimer type.
  • PSP Progressive Supranuclear Paralysis
  • non familia. Appearing late and involving disturbances of several neurotransmitters.
  • PSP is characterized by dementia with postural instability, rigidity, bradykinesia associated , accompanied by supranuclear ophthalmoplegia. This disease appears in approximately 4% of patients with Parkinsonism. There is currently no treatment for this disease. Palliative or symptomatological therapies have no satisfactory effect.
  • faroxan 2- (2-ethyl-2,3 dihydrobenzo-furanyl) - 2-imidazoli
  • This compound is described in patent application GB-2 102 422 as well as its therapeutic application as an antidepressant and antimigraine drug.
  • This compound and its derivatives are also described in patent application WO 92/05171 where the action of the levorotatory enantiomer for treating diabetes is demonstrated, as an agent blocking potassium channels.
  • the present invention relates to the use of Efaroxan and its derivatives for the preparation of a medicament intended for the treatment of senile dementia of the Alzheimer type, of pre-Alzheimer syndrome, of supra-nuclear progressive paralysis and of other neurodegenerative diseases. - tives.
  • Efaroxan and its derivatives is meant the compound of formula I
  • R 1 represents a hydrogen atom, a linear or branched C 1 -C 6 alkyl radical
  • R 2 represents a hydrogen atom, a methyl, chloro, bromo or fluoro group
  • R 3 represents a hydrogen atom, a methyl, hydroxy, methoxy, fluoro, chloro, or bromo group, and its therapeutically acceptable salts, its racemic or its optically active isomers.
  • R 2 and R 3 represent a hydrogen atom and R 1 represents an ethyl, n-propyl or i-propyl group.
  • the compound of general formula I is chosen from the following compounds:
  • Scopolamine a central antagonist, administered before the first training session for passive avoidance behavior, induces a dose-dependent amnesia measurable 48 hours later during a second session.
  • the following table shows the effect of Efaroxan in the presence of scopolamine, in a dose-dependent manner, the increase in time that the rat takes to enter from a lit compartment to a dark compartment where it receives a small electric shock.
  • the percentage of the effect is indicated in the 3rd column.
  • compositions are administered orally in the form of capsules or tablets dosed from 1 to 100 mg of active principle, more particularly from 2, 5 and 20 mg per capsule or by intravenous route in the form of injectable solution dosed with 0.1 10 mg of faroxan.
  • Efaroxan has been administered at a dose of 2 to 20 mg per dose per day for 6 months, to patients who have manifested memory problems, the symptoms of cognitive deficits and behavioral disorders suggesting a pre- Alzheimer's.
  • the results on the overall symptomatology showed a benefit in 30% of the cases.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Steroid Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/FR1994/000841 1993-07-09 1994-07-07 Utilisation de l'efaroxan et de ses derives pour la fabrication de medicaments destines au traitement des maladies neurodegeneratives WO1995001791A2 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
DE69421705T DE69421705T2 (de) 1993-07-09 1994-07-07 Verwendung von Efaroxan und dessen Derivaten zur Herstellung eines Arzneimittels zur Behandlung neurogenerativer Erkrankungen
CA002166781A CA2166781A1 (fr) 1993-07-09 1994-07-07 Utilisation de l'efaroxan et de ses derives pour la fabrication de medicaments destines au traitement des maladies neurodegeneratives
EP94921698A EP0707477B1 (de) 1993-07-09 1994-07-07 Verwendung von Efaroxan und dessen Derivaten zur Herstellung eines Arzneimittels zur Behandlung neurogenerativer Erkrankungen
JP50386595A JP3494651B2 (ja) 1993-07-09 1994-07-07 神経変性疾患の治療を目的とする医薬生成物の製造のためのエファロキサンおよびその誘導体の使用
NZ268914A NZ268914A (en) 1993-07-09 1994-07-07 Use of efaroxan and derivatives to prepare medicaments for treating neurodegenerative diseases especially alzheimer's disease
US08/581,516 US5661172A (en) 1993-07-09 1994-07-07 Use of efaroxan and derivatives thereof for the treatment of Alzheimer's disease
AU72308/94A AU688346B2 (en) 1993-07-09 1994-07-07 Use of efaxoran and its derivatives for the production of drugs for treating neurodegenerative diseases
DK94921698T DK0707477T3 (da) 1993-07-09 1994-07-07 Anvendelse af Efaxoran og derivater deraf til fremstilling af lægemidler beregnet til behandling af neurodegenerative sygdo
GR20000400227T GR3032531T3 (en) 1993-07-09 2000-02-02 Use of efaxoran and its derivatives for the production of drugs for treating neurodegenerative diseases

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9308497A FR2707166B1 (fr) 1993-07-09 1993-07-09 Utilisation de l'efaroxan et de ses dérivés pour la fabrication de médicaments destinés au traitement de maladies neurodégénératives et leur progression .
FR93/08497 1993-07-09

Publications (2)

Publication Number Publication Date
WO1995001791A2 true WO1995001791A2 (fr) 1995-01-19
WO1995001791A3 WO1995001791A3 (fr) 1995-03-09

Family

ID=9449128

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FR1994/000841 WO1995001791A2 (fr) 1993-07-09 1994-07-07 Utilisation de l'efaroxan et de ses derives pour la fabrication de medicaments destines au traitement des maladies neurodegeneratives

Country Status (14)

Country Link
US (1) US5661172A (de)
EP (1) EP0707477B1 (de)
JP (1) JP3494651B2 (de)
AT (1) ATE186640T1 (de)
AU (1) AU688346B2 (de)
CA (1) CA2166781A1 (de)
DE (1) DE69421705T2 (de)
DK (1) DK0707477T3 (de)
ES (1) ES2140544T3 (de)
FR (1) FR2707166B1 (de)
GR (1) GR3032531T3 (de)
NZ (1) NZ268914A (de)
PT (1) PT707477E (de)
WO (1) WO1995001791A2 (de)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2752163A1 (fr) * 1996-08-12 1998-02-13 Pf Medicament Utilisation de l'efaroxan pour la fabricaton de medicament destine au traitement de la maladie de huntington
US8188126B2 (en) 2002-05-16 2012-05-29 Pierre Fabre Medicament Imidazolic compounds and use thereof as alpha-2 adrenergic receptors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI251813B (en) * 2001-11-09 2006-03-21 Via Tech Inc Method for protecting phase lock loop in optical data-reading system
WO2006124770A2 (en) * 2005-05-13 2006-11-23 The Feinstein Institute For Medical Research Treatment of sepsis and inflammation with alpha2a adrenergic antagonists

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0071368A1 (de) * 1981-07-28 1983-02-09 Reckitt And Colman Products Limited Imidazolinderivate
US4855308A (en) * 1987-12-04 1989-08-08 Warner-Lambert Company Method of treating senile cognitive decline with N'-substituted aminopyridine adrenergic agents
EP0486385A1 (de) * 1990-11-14 1992-05-20 Adir Et Compagnie Imidazol-Derivate, Verfahren zu deren Herstellung und diese enthaltende Zusammenstellungen

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4855385A (en) * 1988-06-22 1989-08-08 The Dow Chemical Company Monocarboxylic acid derivatives of aliphatic based epoxy resins

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0071368A1 (de) * 1981-07-28 1983-02-09 Reckitt And Colman Products Limited Imidazolinderivate
US4855308A (en) * 1987-12-04 1989-08-08 Warner-Lambert Company Method of treating senile cognitive decline with N'-substituted aminopyridine adrenergic agents
EP0486385A1 (de) * 1990-11-14 1992-05-20 Adir Et Compagnie Imidazol-Derivate, Verfahren zu deren Herstellung und diese enthaltende Zusammenstellungen

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ARCH.INT.PHARMACODYN.THER., vol.277, no.2, 1985 pages 180 - 191 G.JOLY ET AL. 'Antagonistic Effects of S9871 or (imidazolinyl-2)-2-dihydro 2,3 benzofurane and its Stereoisomers on Some Central and Peripheral Actions of alpha2-Agonists' *
BEHAV.NEURAL BIOL., vol.51, no.3, Mai 1989 pages 401 - 411 S.J.SARA ET AL. 'Idazoxan, an alpha2-Antagonist, Facilitates Memory Retrieval in the Rat' *
J.MED.CHEM., vol.27, no.5, 1984 pages 570 - 576 C.B.CHAPLEO ET AL. 'Alpha-Adrenoreceptor Reagents. 2. Effects of Modification of the 1,4-Benzodioxan Ring System on alpha-Adrenoreceptor Activity' *
J.PSYCHOPHARMACOL., vol.4, no.2, 1990 pages 90 - 99 S.L.DICKINSON ET AL. 'Specific alpha2-adrenoceptor antagonists induce behavioural activation in the rat' *
NEUROCHEM.INT., vol.18, no.1, 1991 pages 137 - 140 H.DE VOS ET AL. 'EFAROXAN (RX 821037) IS A POTENT AND SELECTIVE alpha2-ADRENOCEPTOR ANTAGONIST IN HUMAN FRONTAL CORTEX MEMBRANES' *
PSYCHOPHARMACOLOGY, vol.89, no.4, 1986 page S31 S.J.SARA ET AL. 'ENHANCEMENT OF COGNITIVE FUNCTION IN THE RAT BY ALPHA2 ANTAGONISTS OR ELECTRICAL STIMULATION OF THE LOCUS COERULEUS' *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2752163A1 (fr) * 1996-08-12 1998-02-13 Pf Medicament Utilisation de l'efaroxan pour la fabricaton de medicament destine au traitement de la maladie de huntington
WO1998006393A1 (fr) * 1996-08-12 1998-02-19 Pierre Fabre Medicament Utilisation de l'efaroxan pour la fabrication de medicament destine au traitement de la maladie de huntington
US6153638A (en) * 1996-08-12 2000-11-28 Pierre Fabre Medicament Use of efaroxan for producing medicine for treating huntington 's disease
US8188126B2 (en) 2002-05-16 2012-05-29 Pierre Fabre Medicament Imidazolic compounds and use thereof as alpha-2 adrenergic receptors

Also Published As

Publication number Publication date
WO1995001791A3 (fr) 1995-03-09
JP3494651B2 (ja) 2004-02-09
CA2166781A1 (fr) 1995-01-19
DK0707477T3 (da) 2000-05-15
AU7230894A (en) 1995-02-06
NZ268914A (en) 1999-06-29
ES2140544T3 (es) 2000-03-01
DE69421705D1 (de) 1999-12-23
FR2707166A1 (fr) 1995-01-13
AU688346B2 (en) 1998-03-12
US5661172A (en) 1997-08-26
FR2707166B1 (fr) 1995-09-29
ATE186640T1 (de) 1999-12-15
EP0707477B1 (de) 1999-11-17
DE69421705T2 (de) 2000-06-29
JPH08512305A (ja) 1996-12-24
EP0707477A1 (de) 1996-04-24
PT707477E (pt) 2000-04-28
GR3032531T3 (en) 2000-05-31

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